Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test.

Khisti RT, Chopde CT, Jain SP.

Department of Pharmaceutical Sciences, Nagpur University Campus, 440 010, Maharashtra, Nagpur, India.

The present study aimed to examine the antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) using the forced swim test in mice. Intracerebroventricular (ICV, 1 or 2 microg/mouse) or intraperitoneal (IP, 0.5, 1, or 2 mg/kg) administration of 3alpha, 5alpha THP dose-dependently reduced the duration of immobility in forced swim test without accompanying changes in ambulatory or rearing behaviors in the open-field test. The antidepressant-like effect of 3alpha, 5alpha THP (1 microg/mouse, ICV) was potentiated by prior administration of the GABA(A) receptor agonist, muscimol (0. 5 mg/kg, IP) and blocked by prior administration of GABA(A) receptor antagonist, bicuculline (1 mg/kg, IP). Administration of the agonist at diazepam binding inhibitor receptors, 4'-chlorodiazepam (4'CD, 15 mg/kg, IP) or N,N-di-n-hexyl-2-(4-fluorophenyl)-indol-3-acetamide (FGIN 1-27, 1 or 2 microg/mouse, ICV), the 11beta-hydroxylase inhibitor, metyrapone (150 mg/kg, IP and 1 or 2 microg/mouse, ICV) and the selective serotonin reuptake inhibitor (SSRI), fluoxetine (20 mg/kg, IP), which are known to increase the endogenous level of neurosteroids, also reduced the duration of immobility in forced swim test. The tricyclic antidepressant, imipramine (20 mg/kg, IP), which does not increase the 3alpha, 5alpha THP in the brain, also reduced the immobility time. While the antidepressant-like effect of fluoxetine, which is known to selectively increase the brain content of 3alpha, 5alpha THP, was either blocked partially by bicuculline (1 mg/kg, IP) or potentiated by muscimol (0.5 mg/kg, IP), the antidepressant-like effect of imipramine was not modified by bicuculline. These results demonstrate the antidepressant-like effect of the neurosteroid 3alpha, 5alpha THP, and suggest further evaluation for its development as a new class of antidepressant drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11113493&dopt=Abstract antidepressant




Anti-depressant action of melatonin in chronic forced swimming-induced behavioral despair in mice, role of peripheral benzodiazepine receptor modulation.

Raghavendra V, Kaur G, Kulkarni SK.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, 160014, Chandigarh, India.

The possible antidepressant effect of physiological and pharmacological doses of melatonin was investigated in the Porsolt forced swimming-induced behavioral despair test. The duration of immobility period of BALB/c and C57BL/6J mice during a 6-min swim test was measured at noon (11:00-12:00 h), early dark (20:00-21:00 h) and at midnight (1:00-2:00 h), respectively. The circadian time cycle did not alter the duration of immobility in either strains of mice. Similarly, exogenously administered melatonin (10-1000 microg/kg congruent with 50 nM to 5 microM/mouse), a dose that could act on high affinity melatonin receptors, did not modify the duration of immobility period at any of the time intervals studied in either strains of the mice. This suggested that neither circadian variation influenced the duration of immobility period of BALB/c and C57BL/6J mice nor at physiological doses melatonin showed any anti-depressant action. Acute administration of higher doses of melatonin (2.5-10 mg/kg) failed to induce any anti-depressant activity in mice which were subjected to forced swimming test for the first time. However, daily administration of melatonin (2.5-10 mg/kg) prior to swimming test significantly reversed the increase in immobility period that was observed on chronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAergic drugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test. The anti-depressant action of melatonin was sensitive to reversal by peripheral BZ receptor antagonist, PK11195. Whereas, flumazenil failed to reverse the anti-depressant action of melatonin, thereby suggesting that central BZ receptor were not involved in its action. In conclusion the study showed that at pharmacological doses melatonin has anti-depressant action in chronic forced swimming-induced despair behavior by an action involving peripheral BZ receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11115737&dopt=Abstract antidepressant




Does placebo help establish equivalence in trials of new antidepressants?

Barbui C, Violante A, Garattini S.

Laboratory of Epidemiology and Social Psychiatry, WHO Collaborating Centre for Research and Training in Mental Health, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.

Clinical trials of new antidepressants usually compare a new drug to a reference antidepressant and to a placebo. The placebo is intended to validate the trial in the case of a no-difference outcome, i.e., it helps in assessing equivalence. The aim of the present paper is to test whether placebo has indeed helped establish equivalence of effect in comparative trials of new antidepressants. We carried out an example of sample size determination first in a trial to show a difference between the new and control drug, and second in a trial to assess equivalence between two competing drugs. Finally, we retrospectively calculated the maximum difference accepted as equivalence of effect in published trials of new antidepressants. Assuming a response rate to antidepressants of 70%, 294 subjects for each treatment group are needed to show a 10% difference between two antidepressant drugs and more than 1,300 to assess equivalence at a 5% level of delta, the maximum difference acceptable as equivalence of effect. The level of delta in published trials of new antidepressants ranges between 12 and 43%, suggesting they cannot claim to demonstrate equivalence of effect. Therefore, the presence of a placebo arm for comparison didn't help establish whether both drugs really worked the same way. Comparative trials of new antidepressants should adopt a two-arm design, a suitable number of patients and a high standard in the experimental design in order to minimise possible control-event rate variation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10951612&dopt=Abstract antidepressant




Antioxidant defense against antidepressants in C6 and 1321N1 cells.

Slamon ND, Pentreath VW.

Department of Biological Sciences, University of Salford, M5 4WT, Salford, UK.

The effects of pretreatment with the antioxidants reduced glutathione (GSH), ascorbate (ASC), Trolox (TROL), and combined ascorbate and Trolox (ASC/TROL) exposure on the acute (24 h) toxicities (EC50 value) of the antidepressants amitriptyline, imipramine (tricyclic antidepressants), fluoxetine (a selective serotonin reuptake inhibitor; SSRI), and tranylcypromine (a monoamine oxidase inhibitor; MAOI) were determined in the rat (C6) glioma and human (1321N1) astrocytoma cell lines using the neutral red uptake assay. The effects of pretreatment with buthionine-[S, R]-sulfoximine (BSO), and manipulation of intracellular cyclic AMP (cAMP) using isoproterenol (beta-receptor agonist), 3-isobutyl-1-methylxanthine (IBMX; a phosphodiesterase inhibitor), and dibutyryl cyclic AMP (dBcAMP; cAMP analogue) on antidepressant toxicity were also determined. Protective responses were observed after antioxidant treatments and manipulation of cAMP in both C6 cells pretreated with dBcAMP (+dBcAMP) and 1321N1 cells not pretreated with dBcAMP (-dBcAMP), with a few exceptions in 1321N1 cells (-dBcAMP). Some protective responses occurred in C6 cells (-dBcAMP) and 1321N1 cells (+dBcAMP) after isoproterenol and combined IBMX/isoproterenol pretreatment but not after just IBMX pretreatment. Pretreatment with BSO enhanced toxicity with the exception of fluoxetine. The antidepressants caused increases in intracellular GSH in the C6 cells at subcytotoxic concentrations, with decreases in GSH occurring at higher concentrations. Cytotoxicity of the antidepressants may be partly mediated through oxidative stress with alterations in signal transduction pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10967317&dopt=Abstract antidepressant




Comparison of self-reported and physician-reported antidepressant medication use.

Cotterchio M, Kreiger N, Darlington G, Steingart A.

Division of Preventive Oncology, Cancer Care Ontario, Toronto, Canada.

PURPOSE: Self-reported medication histories obtained in pharmacoepidemiologic case-control studies are subject to non-differential misclassification and to recall bias. The accuracy of self-reported antidepressant medication use has never been evaluated, but it is important in light of the hypothesis that antidepressant medications may be associated with cancer risk. METHODS: Within a case-control study of several cancer sites, we compared self-reported antidepressant medication use with antidepressant use recorded in physicians' records. All female cases (n = 147) and controls (n = 119) who reported antidepressant medication use, and a 10% random sample (n = 114) of those who reported no antidepressant use, were asked to provide consent to contact, and the name(s) of their physician(s). These physicians completed a data abstraction form including information on antidepressant prescriptions recorded in patients' medical records. RESULTS: Substantial agreement was found between subject- and physician-reported antidepressant medication use (kappa = 0.60 [95% confidence interval (CI), 0.47-0.74]; agreement = 80%), and use of specific antidepressant medications (agreement ranged from 82 to 100%), while moderate agreement was observed for duration of use (weighted kappa = 0.56 (95% CI, 0.32-0.79)), and date of first use [weighted kappa = 0.48 (95% CI, 0.23-0.72)]. The level of agreement did not differ markedly between cases and controls, except for duration of use, where agreement was somewhat greater for cases. CONCLUSIONS: The similar level of agreement among cases and controls suggests that differential misclassification (e.g., recall bias) is unlikely in the reporting of most aspects of antidepressant medication use by women. Furthermore, the overall accurate self-reporting of antidepressant use suggests that there should be minimal non-differential antidepressant exposure misclassification.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10976854&dopt=Abstract antidepressant




Increased rate of trazodone prescribing with bupropion and selective serotonin-reuptake inhibitors versus tricyclic antidepressants.

Clark NA, Alexander B.

College of Pharmacy, University of Iowa, Iowa City, USA.

OBJECTIVE: To determine whether trazodone is prescribed significantly more often with selective serotonin-reuptake inhibitors (SSRIs) and bupropion than with tricyclic antidepressants (TCAs). METHODS: A retrospective analysis of Iowa City Department of Veteran's Affairs prescription records from March 1, 1995, to March 1, 1998, was performed. Antidepressants prescribed only by psychiatrists were included. Concomitant use was defined as trazodone prescribed on the same date or up to 42 days after the fill date of the primary antidepressant. STATISTICS: All comparisons used 2 x 2 chi 2 contingency table. Significance level was set at p < 0.05. RESULTS: Significantly more patients were prescribed trazodone concurrently with bupropion and SSRI antidepressants than with TCAs. Trazodone was prescribed significantly more often for patients receiving an SSRI (p = 0.0001, chi 2 = 14.59) or bupropion (p = 0.0295, chi 2 = 4.74) than for patients receiving a TCA. There was no significant difference in trazodone use between the patients taking SSRIs or bupropion. The percent of patients that received an SSRI, bupropion, or a TCA in combination with trazodone was 27%, 23%, and 13%, respectively. Overall, 23.7% of patients received trazodone concomitantly with a primary antidepressant. DISCUSSION: The effects of antidepressants on sleep and on sleep scores of depression rating scales are reviewed. The clinical implications of these findings are discussed. The literature addressing the effects of antidepressants on sleep and on sleep scores of depression rating scales is summarized. Although sleep studies suggest that SSRIs may not improve sleep as well as a TCA, clinical studies do not often support these findings. Several studies report that bupropion may not improve sleep parameters as well as doxepin or trazodone. The clinical implications of these findings are discussed. CONCLUSIONS: We have demonstrated that our clinicians prescribe trazodone at a significantly higher rate with an SSRI or bupropion than with a TCA. The exact reason for this difference is not known. If trazodone is used during the first six weeks of an initial antidepressant treatment trial, it should be discontinued to determine whether the patient's sleep disturbance has responded to the primary antidepressant. More comparison studies among the newer antidepressants and between classes of antidepressants concerning their effects on sleep in the depressed patient need to be performed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10981245&dopt=Abstract antidepressant




Role of the neurotransmitter reuptake-blocking activity of antidepressants in reversing chloroquine resistance in vitro in Plasmodium falciparum.

Taylor D, Walden JC, Robins AH, Smith PJ.

Department of Pharmacology, University of Cape Town Medical School, Observatory 7925, South Africa.

Since the discovery of the chloroquine (CQ) resistance reversal properties of several different, structurally unrelated classes of compounds, including antidepressants, the way is again open to employ the aminoquinoline drugs to combat malaria effectively. In this study, CQ sensitivity was restored to varying extents in vitro in the CQ-resistant Plasmodium falciparum strain RSA11 by using the antidepressants amitriptyline, citalopram, oxaprotiline, and nomifensine. The 50% inhibitory concentrations (IC(50)) of CQ were reduced from 360 to as low as 11 nM when antidepressants were present. These particular antidepressants are highly specific for blocking the ATP-binding cassette transport protein-mediated reuptake of different neurotransmitters at the synaptic level. This study was aimed at determining the extent to which the neurotransmitter reuptake-blocking properties of these antidepressants play a role in the reversal process. None of the compounds or CQ-antidepressant combinations tested had innate antimalarial activity. No chemosensitizer or combination showed an increased CQ accumulation or significant shift in the IC(50) in the CQ-sensitive clone D10. Of the compounds tested, citalopram, a highly specific serotonin reuptake blocker, produced the largest shift observed in the IC(50) for the resistant isolate RSA11. No particular class of antidepressant was found to be better than any other at restoring CQ sensitivity. We conclude that the resistance-reversing properties of these compounds do not correlate with their activities as reuptake blockers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10991845&dopt=Abstract antidepressant




Antidepressant-like effect of different estrogenic compounds in the forced swimming test.

Estrada-Camarena E, Fernandez-Guasti A, Lopez-Rubalcava C.

Depto de Farmacobiologia CINVESTAV-IPN, Calzada de los Tenorios 235, Col Granjas Coapa, Deleg Tlalpan, CP 14330 Mexico DF, Mexico. estrada imp.edu.mx

The present study evaluated the possible antidepressant-like action of the natural estrogen 17beta-estradiol (E(2), 2.5-10 microg/rat), the synthetic steroidal estrogen ethinyl-estradiol (EE(2), 1.25-10.0 microg/rat), and the nonsteroidal synthetic estrogen, diethyl-stilbestrol (DES, 0.25-1.0 mg/rat) in ovariectomized adult female Wistar rats using the forced swimming test (FST). The behavioral profile induced by the estrogens was compared with that induced by the antidepressants fluoxetine (FLX, 2.5-10 mg/kg) and desipramine (DMI, 2.5-10 mg/kg). In addition, the temporal course of the antidepressant-like action of the estrogenic compounds was analyzed. FLX and DMI induced an antidepressant-like effect characterized by a reduced immobility and increased swimming for FLX and decreased immobility and increased climbing for DMI. Both E(2) and EE(2) produced a decrease in immobility and an increase in swimming, suggesting an antidepressant-like action. DES did not affect the responses in this animal model of depression at any dose tested. The time course analysis of the actions of E(2) (10 microg/rat) and EE(2) (5 microg/rat) showed that both compounds induced an antidepressant-like effect observed 1 h after their injection lasting for 2-3 days.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12637949&dopt=Abstract antidepressant